A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

作者：Aguilar Angelo; Zhou Haibin; Chen Jianfang; Liu Liu; Bai Longchuan; McEachern Donna; Yang Chao Yie; Meagher Jennifer; Stuckey Jeanne; Wang Shaomeng^*

来源：Journal of Medicinal Chemistry, 2013, 56(7): 3048-3067.

DOI：10.1021/jm4001105

Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K-i values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.

• 出版日期2013-4-11